Pharmaceutical administration form for peptides, process for its preparation, and use

ABSTRACT

A method for preventing aggregation of an LHRH antagonist in a pharmaceutical composition. The method comprises combining the LHRH antagonist in the form of an acetate, gluconate, glucuronate, lactate, citrate, ascorbate, benzoate or phosphate salt at least one of the acids for forming the salts in free acid form.

The invention relates to novel galenic forms for the parenteraladministration of peptides prone to aggregation, in particular of LHRHanalogues or LHRH antagonists and agonists, and processes for theirpreparation, and use.

EP 0 299 402 discloses the use of pharmaceutically active decapeptidessuch as SB-030, SB-075 (cetrorelix) and SB-088 in the form of theirpharmaceutically acceptable, non-toxic acid addition salts such ashydrochlorides, hydrobromides, sulphates, phosphates, fumarates,gluconates, tannates, maleates, acetates, citrates, benzoates,succinates, alginates, pamoates, ascorbates and tartrates etc.

JP 06321800-A furthermore discloses a lyophilized peptide or proteinpreparation which contains gluconate salts as stabilizers. In oneexample, the solution contains 2.5% of magnesium gluconate, the activecompounds described being, inter alia, vasopressin, LHRH and insulin.

It is known from the literature, inter alia from Powell, M. F.,Pharmaceutical Research, 1258-1263(8) 1991; Dathe M. Int. J. PeptideProtein Res. 344-349(36) 1990, and Szejtli, J. Pharmaceutical TechnologyInternational 16-22, 1991, that oligopeptides, namely particularly thosehaving a terminal acid amide function, are prone to gel formation.

EP 0 611 572 describes a preparation process for a lyophilizate of apeptide having 3-15 amino acids, according to which 100-10,000 parts byweight of the peptide are dissolved in acetic acid and treated withbulking agents such as mannitol, and then lyophilized in order to obtaina sterile-filtered lyophilizate of the peptide and to avoid gelformation.

DE A 195 42 873 describes pharmaceutical administration forms ofcomplicated composition in the form of microparticles, according towhich an ABA triblock copolymer is used whose A block is a polymer ofmilk [sic] and glycolic acid and whose B polymer is a polyethyleneglycol chain, together with an additive from the group consisting of theserum proteins, polyamino acids, cyclodextrins, cyclodextrinderivatives, saccharides, amino sugars, amino acids, detergents orcarboxylic acids and mixtures of these substances. After inclusion ofsmall or aggregation-sensitive amounts of polypeptide, themicroparticles described should also release the polypeptidecontinuously over a relatively long period.

DD 141 996 describes the preparation of pharmaceutical forms of nativeLHRH which are stable over a relatively long period and comply with therequirements for a parenterally administerable preparation. The keypoint here is the improvement in the shelf life of these preparations(page 2, lines 19-23). No statement is made about the filterability ofthe solutions. Moreover, to improve the shelf life buffer substances(also acetic acid) are also employed to establish a pH range of pH3.5-6.5. The problem of preparing sterile lyophilizates from gel-formingpeptide salts is not solved there.

EP 0 175 506 treats an aqueous solution of the peptide with 1N aceticacid and then lyophilizes it in order to obtain the acetate salt of thepeptide. The subject of this application is thus the synthesis of thepeptide salts.

However, it has been shown that in the case of the known acetate saltsof the peptides prone to aggregation, such as the LHRH antagonists, thepreparation of sterile solutions for parenteral administration by meansof filtration, especially at high concentrations, is indeed possible,but aggregates can form shortly before injection after the dissolutionof the lyophilizate. The aggregates then lead to aconcentration-dependent lowering of the bioavailability from a peptideconcentration of 0.5 mg/ml.

The problem mentioned occurs not only with injection solutions which areadministered for the purpose of rapid release of active compound, but isalso observed with injection preparations which exhibit delayed release.Thus peptides, incorporated in matrices which should control the releaseof active compound, can have an undesirably low release on account oftheir proneness to aggregation. Thus the bioavailability is also loweredhere.

Starting from the fact that the preferred administration ofpharmaceutically active peptides such as LHRH agonists and antagonists,for example antarelix and cetrorelix, is the parenteral pharmaceuticalform, a need exists for the provision of stable injection preparationshaving acceptable bioavailability, which can be conveniently prepared,sterile-filtered and formulated. This applies in particular to injectionpreparations in the form of reconstituted lyophilizates of solublepeptide salts and to microparticles, microcapsules or implants.

This is all the more of importance in consideration of the varied areasof use of the LHRH antagonists, which are becoming more and more known.

A wider selection of parenterally, in particular subcutaneously,injectable, stable peptide solutions is desirable in view of the rapidlygrowing indication areas of this class of substance.

Pharmaceutical administration forms suitable for parenteraladministration, which contain peptides prone to aggregation in dissolvedor dispersed form, have now been developed which are distinguished inthat the peptides are present in the form of their acetate, gluconate,glucuronate, lactate, citrates, ascorbate, benzoate or phosphate saltsand that these administration forms can additionally contain one of thejust-mentioned acids as free acids, and, if appropriate, furtheradditives and excipients from the class consisting of the acids,surface-active substances, polymers, lipids or sugars.

These pharmaceutical administration forms can be present in dissolved ordispersed form in water or in aqueous solvent mixtures.

According to a further embodiment of the invention, the pharmaceuticaladministration forms can also be present in dissolved or dispersed formin a physiologically tolerable oil, preferably medium-chaintriglycerides (neutral oils, Miglyol®) or castor oil, sesame oil,cottonseed oil, maize oil, peanut oil, olive oil or in mixtures of suchoils.

The peptides employed are the LHRH antagonists antide, A-75998,ganirelix and Nal-Glu antagonist, but in particular cetrorelix,antarelix and the antagonists according to the Patents U.S. Pat. No.5,942,493 and DE 19911771.3.

Acids employed in the excipient function are gluconic acid, glucuronicacid, galacturonic acid, glucaric acid, citric acid, ascorbic acid andamino acids.

It is thus possible to suppress the aggregation of the peptide and thusto fulfil the requirements for a preparation having goodbioavailability, and thus to enrich the pharmaceutical wealth and to doso with efficient galenic technology.

It has further surprisingly been found that by the addition of gluconic,glucuronic, citric, lactic or ascorbic acid, the stability of variouscetrorelix salts is moreover considerably improved.

According to the invention, the preparation and formulation ofsterile-filtered, stable preparations is thus possible without problems.

It is additionally advantageous to add suitable excipients. Theseexcipients can be acids, surface-active substances, polymers, lipids orsugars. Examples of acids are gluconic acid, glucuronic acid,galacturonic acid, glucaric acid, lactic and citric acid, ascorbic acidand amino acids. Surface-active substances employed can be polyethyleneglycol 12-(hydroxy)stearate (Solutol®), polyoxyethylene ricinoleate(Cremophor®), polysorbates, poloxamers, phospholipids, lecithins orbenzalkonium chloride. Suitable polymers are albumins, polyethyleneglycols, cellulose derivatives, starch derivatives orpolyvinylpyrrolidone. Examples of sugars are cyclodextrins andcyclodextrin derivatives. ‘Chaotropic’ substances such as urea can alsoserve as additives and/or excipients.

The area of use of the preparations according to the invention is inparticular in the prevention and therapy of all sex hormone-dependentconditions and diseases which can be influenced by LHRH analogues, i.e.LHRH agonists and LHRH antagonists. Those to be emphasized here are:

-   -   benign prostate hyperplasia, carcinoma of the prostate,        precocious puberty, hirsutism, endometrial hyperplasia and its        accompanying symptoms, endometrial carcinoma, in-vitro        fertilization (IVF/COS/ART), contraception, premenstrual        syndrome (PMS), uterine myomatosis, breast cancer, tubal        obstruction (PTO), ovarian cancer, carcinoma of the uterus. The        following substances are particularly preferred as LHRH        antagonists for the composition according to the invention:    -   cetrorelix, antarelix, antide, A-75998, ganirelix, the Nal-Glu        antagonist, and LHRH antagonists according to the Patents U.S.        Pat. No. 5,942,493 and DE 19911771.3.

EXAMPLE 1

By means of polarization microscopy, aggregation investigations werecarried out on solutions of various cetrorelix salts without or withaddition of excipients.

In the polarization light microscope with crossed polarizers, aggregatedpeptide solutions show images which are very similar to those ofliquid-crystalline structures. In contrast to this, aggregate-freepeptide solutions produce no such effects. TABLE 1 Influence of agluconic acid addition on the aggregation behaviour of cetrorelixacetate solutions. Gluconic acid Concentration in the of cetrorelixreconstitution Days without acetate, mg/ml medium, %: pH aggregation 2.50 4.7 1 2.5 0.0071 4.5 2 2.5 0.071 3.7 2 2.5 0.71 3.1 12

Thus the addition of gluconic acid causes an improvement in thestability of cetrorelix acetate solutions by delaying or preventingaggregation.

Further experiments concentrated on cetrorelix gluconate without or withaddition of gluconic acid. The most important results are summarized inTable 2. TABLE 2 Aggregation behaviour of various solutions which wereprepared from cetrorelix gluconate bulk Gluconic acid addition:Concentration Yes No of Days Days cetrorelix, without without mg/ml pHaggregation pH aggregation 2.5 3.0 >30 5 3.6 4 4.8 1 5 3.8 4 4.7 1 7.53.4 1 4.7 0 7.5 3.7 1 4.8 0

Cetrorelix gluconate thus offers advantages in comparison with theacetate salt. The addition of gluconic acid increases the shelf life ofcetrorelix gluconate solutions.

Moreover, the stabilizing influence of glucuronic acid on cetrorelixacetate solutions and, as a further salt, also cetrorelix glucuronate,was tested for its aggregation behaviour. The results are summarized inTable 3. TABLE 3 Aggregation behaviour of variously concentratedsolutions of cetrorelix acetate and cetrorelix glucuronate without orwith addition of glucuronic acid. Glucuronic acid addition:Concentration Yes No of Days Days cetrorelix, without without Salt formmg/ml pH aggregation pH aggregation Acetate 2.5 3.0 >21 4.7 0 Acetate 53.0 0 Glucuronate 2.5 2.9 >30 4.5 3 Glucuronate 5 2.7 >30 4.6 0

Also, by the replacement of the acetate salt by a glucuronate salt,significant improvements can be achieved with respect to the aggregationstability of cetrorelix similarly to with the gluconate salt. By theaddition of glucuronic acid to cetrorelix glucuronate solutions, theaggregation stability of these solutions can be even further improved.TABLE 4 Aggregation-free duration in days of cetrorelix acetatesolutions after addition of 10% of α-cyclodextrin, 20% ofhydroxypropyl-β-cyclodextrin or 20% of γ-cyclodextrin. Concen- trationof cetrorelix acetate, Hydroxypropyl- mg/ml α-Cyclodextrinβ-cyclodextrin γ-Cyclodextrin 2.5 7 24 98 + (168, 182, 189) 5 0 7 31 +(140, 147, 182) 7.5 0 10  5 + (20, 20, 20) 10 0 2  2 + (4, 4, 4) 15 0  0

By the addition of hydroxypropyl-β-cyclodextrin and particularly ofγ-cyclodextrin, the aggregation stability of cetrorelix acetatesolutions can be significantly improved. TABLE 5 Aggregation-freeduration in days of 2.5 mg/ml cetrorelix gluconate solutions afteraddition of α-cyclodextrin, hydroxypropyl-β-cyclodextrin orγ-cyclodextrin. Concentration of Days without Cyclodextrin typecyclodextrin, % aggregation γ-Cyclodextrin 20 182 6.8 126Hydroxypropyl-β- 20 189 cyclodextrin 6.8 91 α-Cyclodextrin 10 140 5 1

By the addition of hydroxypropyl-β-cyclodextrin or of γ-cyclodextrin,the aggregation stability of cetrorelix gluconate solutions can also besignificantly improved. TABLE 6 Aggregation-free duration in days ofcetrorelix acetate solutions with addition of polyvinylpyrrolidone(Kollidon ® 12 PF or 17 PF). Concentration Days without Days without ofaggregation aggregation cetrorelix, Concentration with Kollidon ® withKollidon ® mg/ml of Kollidon ®, % 12 PF 17 PF 2.5 0 0 0 5 1 2 10 1 2 1577 63 20 84 98 5 15 0 1 20 0 1

Also, by the addition of various types of polyvinylpyrrolidone, theaggregation stability of cetrorelix acetate solutions can besignificantly improved. TABLE 7 Aggregation behaviour of cetrorelixacetate solutions with addition of various excipients assessed by meansof polarization microscopy and according to the optical appearance.Conc. of Conc. of Aggregation Excipient excipient cetrorelix(microscopy) Appearance Solutol ®  5.00% 2.5 mg/ml yes, after clear HS15 14 days solution 10.00% 2.5 mg/ml ≧112 days clear without solutionaggregation 20.00% 2.5 mg/ml ≧112 days clear without solutionaggregation Cremophor ®  5.00% 2.5 mg/ml yes, after clear EL 10 dayssolution 10.00% 2.5 mg/ml ≧112 days clear without solution aggregation20.00% 2.5 mg/ml ≧112 days clear without solution aggregation 20.00%   5mg/ml yes, after 1 clear, day viscose L-glutamic  0.80% 2.5 mg/ml yes,after 2 clear acid days solution, pH 3.8 Glucaric  2.50% 2.5 mg/ml ≧12days clear acid without solution, aggregation pH 2.5 Galacturonic  2.50%2.5 mg/ml ≧12 days clear acid without solution, aggregation pH 2.6

EXAMPLE 2

Cetrorelix bulk material is dissolved in a concentration of 10 mg/ml in30% strength acetic acid and diluted with an aqueous solution of theadditives to a final concentration of 1 mg/ml of peptide in 3% aceticacid. This solution is then sterile-filtered and lyophilized (5 mg pervial).

After reconstitution of these lyophilizates, the solutions (2.5 mg/ml ofcetrorelix) are investgated in the following tests for aggregateformation and release behaviour:

-   -   Polarization microscopy (pol. mic.): days without aggregation.    -   Filterability in %:    -   Cetrorelix solutions are prepared according to a standardized        procedure and filtered through 0.22 μm or 0.45 μm filters by        means of centrifugation. The concentration of cetrorelix in the        filtrate is determined by HPLC and indicated as a % value, based        on the starting concentration before filtration (filterability        in %).    -   in-vitro release form (RRS, release in Ringer's solution):    -   % released after 1 h and after 6 h.    -   The in-vitro release behaviour is determined at 37° C. in a flow        procedure using Ringer's solution as medium. The concentration        measurement is carried out by HPLC. Cetrorelix samples,        corresponding to 10 mg of cetrorelix base, are weighed into the        flow cell, mixed with 4 ml of water and stirred for 10 min.        After addition of 6 ml of Ringer's solution to the sample,        Ringer's solution is pumped uniformly through the flow cell with        a flow of 0.5 ml/min, with stirring.    -   Rat animal experiment: cetrorelix residual content in the muscle        in % of the administered dose 168 h after injection.

Some prepared batches of cetrorelix acetate lyophilizate and thecorresponding test results of 2.5 mg/ml cetrorelix acetate solutionsprepared therefrom are shown in Table 8a. TABLE 8a Batches of cetrorelixPol. mic., RRS, Rat % acetate lyophilizate days 0.22 μm [%] i.m. (5 mg). . . without filterable after after Excipients aggr. [%] 1 h 6 h 168 honly mannitol 0 about (= control) 55 Solutol ®/mannitol 48 100Cremophor ®/mannitol 46 101 Solutol ®/alanine 16 98 17 24Solutol ®/alanine/ 19 101 57 68 5.7 gluconic acidSolutol ®/mannitol/ >45 100 84 88 3.8 gluconic acidCremophor ®/mannitol/ >45 101 gluconic acid Solutol ®/tryptophan/imposs. mannitol Solutol ®/tryptophan/ 6 9.6 gluconic acid Cyclodextrinmolar 2 101 16 27 10 ratio 1:10/mannitol Cyclodextrin molar >45 102 6874 ratio 1:10/mannitol/ gluconic acid Cyclodextrin molar 17 100 68 76ratio 1:30/mannitol Cyclodextrin molar 5 101 39 52 6.3 ratio1:10/alanine/ gluconic acid Mannitol/citric acid 1 102 45 53Solutol ®/mannitol/ >36 100 84 91 7.4 citric acid Solutol ®/alanine/ 199 47 54 citric acid Solutol ®/glycine >36 97 24 31 Solutol ®/urea 21100 32 40 Solutol ®/glycine/ >36 99 82 89 gluconic acidSolutol ®/urea/gluconic >36 100 acid Cremophor ®/alanine/ (36) gluconicacid Cremophor ®/urea/ (36) gluconic acid Pluronic ® F127/mannitol 1 5%Tween ® 80/mannitol >16 Polyethylene glycol 1 4000/mannitolDextran/mannitol 1 Phenylmercury 2 acetate/mannitol

In the examples shown, it is evident that with a large number of thetested excipients from various groups of substances (surface-activesubstances, acids, amino acids, polymers, sugars, sugar alcohols,cyclodextrins, preservatives), stabilizing effects can be achieved invitro (polarization microscopy, filterability, in-vitro release) and invivo individually or with mixtures of these excipients. This reducedtendency to aggregate and thus improved in-vitro release of activecompound also leads in the rat experiment to improved bioavailabilitiesof the peptide active compound and thus to reduced residual contents inthe rat muscle.

Further in-vitro and in-vivo data of batches containing variouscetrorelix salts without or with addition of stabilizing excipients arelisted in Table 8b which follows: TABLE 8b Pol. Cetrorelix salts Conc.of mic Rat % (reconstituted with cetrorelix days RRS, [%] i.m. water)from lyo without after after Excipients mg/ml aggr. 1 h 6 h 168 hAcetate 2.5 0 12 24.5 about 55 Acetate 2.5 0 13 35.9 about 55 Acetate 50 10 35 Acetate reconstituted 2.5 18 50 63.2 15.2 with gluconic acidAcetate + Kollidon ® 2.5 84 15 43.4 20.2 12 PF Acetate + Kollidon ® 2.598 22 50.6 17 PF Acetate + benzalkonium 2.5 6.3 30.3 chloride Acetate +phospholipids 2.5 7.3 23.3 Acetate + γ- 2.5 22.6 44.5 10 cyclodextrin(1:10) Acetate + γ- 2.5 28 56.7 cyclodextrin (1:30) Acetate + γ- 2.535.1 56.6 cyclodextrin (1:50) Acetate + γ- 2.5 >168 34.5 60.2 3.6cyclodextrin (1:90) Acetate + γ- 5 140 19 47.8 cyclodextrin (1:90)Acetate + γ- 7.5 20 cyclodextrin (1:90) Acetate + γ- 10 4 45.2cyclodextrin (1:90) Acetate reconstituted 15 49.1 with gluconic acidGluconate 2.5 18 45.3 Gluconate 2.5 11.3 46 Gluconate 2.5 77.5 83.6reconstituted with gluconic acid Citrate 15 9 20.3 Lactate bulk 20 55.2Embonate 15 13 43

EXAMPLE 3

Cetrorelix formulations which are less prone/slower to aggregate (betterfilterability/polarization microscopy) and exhibit more rapid in-vitrorelease in Ringer's solution precipitate after 168 h in the rat muscleexperiment owing to their lower residual content of cetrorelix. A higherbioavailability is expected of such formulations.

Some results of rat muscle experiments have already been listed inTables 8a and 8b.

In the further rat muscle experiments shown in Table 9, in addition tothe residual content in the muscle, the cetrorelix content in the plasmawas additionally determined. With the aid of these data too, thestabilizing influence of the excipients tested is clear.

Moreover, it was possible by the replacement of the acetate salt byother salt forms of cetrorelix to achieve an improved bioavailabilityand, accompanying this, a reduced residual amount in the rat muscleexperiment. TABLE 9 Cetrorelix Cetrorelix Cetrorelix concentrationcontent in content in of the the muscle the plasma, Substance Dose inj.soln (168 h), % % of the (cetrorelix) (mg/kg) (mg/ml) of the dose doseAcetate + Solutol ® + alanine + gluconic 1.5 2.5 5.7 acid Acetate +Solutol ® + tryptophan + gluconic 1.5 2.5 9.6 acid Acetate +cyclodextrin 1.5 2.5 10.0 83.4 1:10 Acetate + cyclodextrin 1.5 2.5 6.381.8 1:10, alanine, gluconic acid Acetate + Solutol ® + gluconic 1.5 2.53.8 acid Acetate + Solutol ® + citric 1.5 2.5 7.4 acid Acetate 1.5 355.1 92.2 Acetate in 1.5 3 22.3 74.2 Miglyol ® Acetate + benzalkonium1.5 3 76.9 39.8 chloride Acetate + 20% 1.5 3 3.6 106.2 cyclodextrinAcetate + 20% 1.5 3 20.2 88.4 Kollidon ® Acetate + glucuronic 1.5 3 23.6106.1 acid Acetate + gluconic 1.5 3 15.2 95.5 acid Acetate + 20% 3.0 1045.2 60.9 cyclodextrin Acetate 3.0 15 56.5 28.7 Acetate in 3.0 15 24.257.2 Miglyol ® Acetate + 0.025% 3.0 15 10.5 21.4 benzalkon. Acetate +glucuronic 3.0 15 78.1 43.8 acid Acetate + gluconic 3.0 15 49.1 45.5acid Gluconate 1.5 15 37.9 46.9 Gluconate in 1.5 3 24.6 58.0 mannitolGluconate in 1.5 3 25.4 75.2 mannitol Gluconate in 1.5 3 28.8 46.3Miglyol ® Gluconate in 1.5 3 13.2 120.0 gluconic acid Gluconate in 3.015 29.2 gluconic acid Gluconate in 3.0 15 43.5 74.2 gluconic acidGlucuronate 1.5 3 16.5 78.6 Glucuronate 3.0 15 18.8 Lactate 3.0 15 33.272.1 Lactate 1.5 3 30.7 67.1 Citrate lyo/a 1.5 3 22.8 36.6 Citrate in1.5 3 14.8 53.1 Miglyol ® Base 1.5 3 27.2 122.2 Base in Miglyol ® 1.5 338.9 55.9 Benzoate in 1.5 3 34.2 32.7 mannitol Benzoate in 1.5 3 33.121.1 Miglyol ® Phosphate 1.5 3 32.9 22.6

1-17. (canceled)
 18. A method for preventing aggregation of an LHRHantagonist in a pharmaceutical composition for parenteraladministration, comprising the steps of: providing an LHRH antagonistsalt, said LHRH antagonist salt being in the form of an acetate,gluconate, glucuronate, lactate, citrate, ascorbate, benzoate orphosphate salt; dissolving or dispersing said LHRH antagonist salt in acarrier; and including in said carrier a pharmaceutical acceptable acidselected from the group consisting of gluconic acid, glucuronic acid,lactic acid, citric acid, ascorbic acid, benzoic acid and phosphoricacid to form a pharmaceutical composition, whereby aggregation of saidLHRH antagonist in said pharmaceutical composition is suppressed. 19.The method of claim 18, wherein said carrier is water, a physiologicallytolerable oil, or an aqueous solvent mixture.
 20. The method of claim18, further comprising adding an excipient.
 21. The method of claim 20wherein said excipient is selected from the group consisting of gluconicacid, glucuronic acid, galacturonic acid, glucaric acid, citric acid,ascorbic acid, an amino acid, polyethylene glycol 12-(hydroxy)stearate(Solutol®), polyoxyethylene ricinoleate (Cremophor®), polysorbates,poloxamers, phospholipids, lecithins, a preservative, albumins,polyethylene glycols, cellulose derivatives, starch derivatives,polyvinylpyrrolidone, cyclodextrins or its derivatives, sugar alcohols,urea, chaotropic substances, and mixtures thereof.
 22. The method ofclaim 18, wherein said LHRH antagonist salt is present in said carrierin a concentration of higher than about 0.5 mg/ml.
 23. The method ofclaim 18, further comprising incorporating a polymer to delay therelease of said LHRH antagonist.
 24. The method of claim 23, whereinsaid polymer is a homo- or copolymer of lactic or glycolic acid.
 25. Themethod of claim 19, wherein said oil is a medium-chain triglyceride oil,castor oil, sesame oil, cottonseed oil, maize oil, peanut oil, oliveoil, or mixtures thereof.
 26. The method of claim 18, wherein the LHRHantagonist is selected from the group consisting of antide, A-75998,ganirelix, Nal-Glu antagonist, cetrorelix, antarelix and the antagonistswhich are compounds of the following general formulas I, V and VII andthe salts thereof with pharmaceutically acceptable acids

in which n is the number 3 or 4, R¹ is an alkyl group, an alkyloxygroup, an aryl group, a heteroaryl group, an aralkyl group, aheteroaralkyl group, an aralkyloxy group or a heteroaralkyloxy group, ineach case unsubstituted or substituted, R² and R³ independently of oneanother are each a hydrogen atom, an alkyl group, an aralkyl group or aheteroaralkyl group, in each case unsubstituted or substituted, wherethe substitution can in turn consist of an aryl group or heteroarylgroup, or —NR²R³ is an amino acid group, and R⁴ is a group having theformula (II)—(CH₂)_(p)—CO—NR⁵R⁶   (II) in which p is an integer from 1 to 4, R⁵ ishydrogen or an alkyl group and R⁶ is an unsubstituted or substitutedaryl or heteroararyl group, or R⁴ is a ring of the general formula (III)

in which q is the number 1 or 2, R⁷ is a hydrogen atom or an alkylgroup, R⁸ is a hydrogen atom or an alkyl group and X is an oxygen orsulphur atom, where the aromatic or heteroaromatic radicals can bepartially or completely hydrogenated and chiral carbon atoms can havethe R— or S-configuration, and its salts with pharmaceuticallyacceptable acids;Ac-D-Nal(2)¹-D-(pCl)Phe²-D-Pal(3)³-Ser⁴-Tyr⁵-D-Xxx⁶-Leu⁷-Arg⁸-Pro⁹-D-Ala¹⁰-NH₂   (V) in which D-Xxx is an amino acid groupof the general formula (VI)

in which n is the number 3 or 4, R⁴ is a group of the formula (II)

in which p is an integer from 1 to 4, R⁵ is hydrogen or an alkyl groupand R6 is an unsubstituted or substituted aryl group or heteroarylgroup, or R⁴ is a ring of the general formula (III)

in which q is the number 1 or 2, R⁷ is a hydrogen atom or an alkylgroup, R⁸ is a hydrogen atom or an alkyl group and X is an oxygen orsulphur atom, and its salts with pharmaceutically acceptable acids; andA-Xxx¹-Xxx²-Xxx³-Xxx⁴-Xxx⁵-Xxx⁶-Xxx⁷-Xxx⁸-Xxx⁹-Xxx¹⁰-NH₂   (VII) inwhich A is an acetyl or a 3-(4-fluorophenyl)propionyl group, Xxx¹ isD-Nal(1) or D-Nal(2), Xxx²-Xxx³ is D-Cpa-D-Pal(3) or a single bond, Xxx⁴is Ser, Xxx⁵ is N-Me-Tyr, Xxx is D-Cit, D-Hci or a D-amino acid group ofthe general formula (VIII)

in which n is the number 3 or 4, where R¹¹ is a group having the generalformula (IX)—(CH₂)_(p)—CO—NR¹²R¹³   (IX) where p is an integer from 1 to 4, R¹² ishydrogen or an alkyl group and R¹³ is an unsubstituted or substitutedaryl group or heteroaryl group, or R¹¹ is a3-amino-1,2,4-triazole-5-carbonyl group or R¹¹ is a ring of the generalformula (X)

in which q is the number 1 or 2, R¹⁴ is a hydrogen atom or an alkylgroup, R¹⁵ is a hydrogen atom or an alkyl group and X is an oxygen orsulphur atom, Xxx⁷ is Leu or Nle, Xxx⁸ is Arg or Lys(iPr), Xxx⁹ is Proand Xxx¹⁰ is Ala or Sar, and their salts with pharmaceuticallyacceptable acids.
 27. The method of claim 26, wherein A-75998 is thepeptide Detirelix with the sequenceAc-D-Nal-D-(pCl)-Phe-D-Pal-Ser-NMeTyr-D-Lys(Nic)-Leu-Lys(iPr)-Pro-D-Ala-NH₂.28. The method of claim 18, wherein said pharmaceutical composition isan injection preparation.
 29. The method of claim 18, wherein said LHRHantagonist salt is Cetrorelix in the form of its acetate, gluconate orglucuronate salt, wherein said carrier is water and wherein saidpharmaceutically acceptable acid is independently selected from gluconicacid or glucuronic acid.
 30. A method for preparing a pharmaceuticalcomposition for parenteral administration, comprising a pharmaceuticallyeffective amount of an LHRH antagonist dissolved or dispersed in acarrier, and additionally a pharmaceutically acceptable acid, whereinsaid LHRH antagonist is present in the form of an acetate, gluconate,glucuronate, lactate, citrate, ascorbate, benzoate or phosphate salt,and wherein said pharmaceutical acceptable acid is present as free acidindependently selected from gluconic acid, glucuronic acid, lactic acid,citric acid, ascorbic acid, benzoic acid and phosphoric acid, and saidpharmaceutically acceptable acid is added to suppress the aggregation ofthe LHRH antagonist salt, the method comprising the steps of: subjectingan LHRH antagonist salt to double decomposition with acetic acid,gluconic acid, glucuronic acid, lactic acid, citric acid, ascorbic acid,benzoic acid or phosphoric acid to produce a corresponding LHRHantagonist salt in a stoichiometric ratio; dissolving said correspondingLHRH antagonist salt in water to form a solution; sterile-filtering saidsolution to form a sterile-filtered solution; dispensing saidsterile-filtered solution into at least one vial; lyophilizing saidsterile-filtered material in said at least one vial to form alyophilisate; and reconstituting said lyophilisate with a carrier beforethe parenteral administration.
 31. The method of claim 30, wherein saidcarrier is water, a physiologically tolerable oil, or an aqueous solventmixture.
 32. The method of claim 30, further comprising adding anexcipient.
 33. The method of claim 32 wherein said excipient is selectedfrom the group consisting of gluconic acid, glucuronic acid,galacturonic acid, glucaric acid, citric acid, ascorbic acid, an aminoacid, polyethylene glycol 12-(hydroxy)stearate (Solutol®),polyoxyethylene ricinoleate (Cremophor®), polysorbates, poloxamers,phospholipids, lecithins, a preservative, albumins, polyethyleneglycols, cellulose derivatives, starch derivatives,polyvinylpyrrolidone, cyclodextrins or its derivatives, sugar alcohols,urea, chaotropic substances, and mixtures thereof.
 34. The method ofclaim 30, wherein said LHRH antagonist salt is present in said carrierin a concentration of higher than about 0.5 mg/ml.
 35. The method ofclaim 30, further comprising incorporating a polymer to delay therelease of said LHRH antagonist.
 36. The method of claim 35, whereinsaid polymer is a homo- or copolymer of lactic or glycolic acid.
 37. Themethod of claim 31, wherein said oil is a medium-chain triglyceride oil,castor oil, sesame oil, cottonseed oil, maize oil, peanut oil, oliveoil, or mixtures thereof.
 38. The method of claim 30, wherein the LHRHantagonist is selected from the group consisting of antide, A-75998,ganirelix, Nal-Glu antagonist, cetrorelix, antarelix and the antagonistswhich are compounds of the following general formulas I, V and VII andthe salts thereof with pharmaceutically acceptable acids

in which n is the number 3 or 4, R¹ is an alkyl group, an alkyloxygroup, an aryl group, a heteroaryl group, an aralkyl group, aheteroaralkyl group, an aralkyloxy group or a heteroaralkyloxy group, ineach case unsubstituted or substituted, R² and R³ independently of oneanother are each a hydrogen atom, an alkyl group, an aralkyl group or aheteroaralkyl group, in each case unsubstituted or substituted, wherethe substitution can in turn consist of an aryl group or heteroarylgroup, or —NR²R³ is an amino acid group, and R⁴ is a group having theformula (II)—(CH₂)_(p)—CO—NR⁵R⁶   (II) in which p is an integer from 1 to 4, R⁵ ishydrogen or an alkyl group and R⁶ is an unsubstituted or substitutedaryl or heteroararyl group, or R⁴ is a ring of the general formula (III)

in which q is the number 1 or 2, R⁷ is a hydrogen atom or an alkylgroup, R⁸ is a hydrogen atom or an alkyl group and X is an oxygen orsulphur atom, where the aromatic or heteroaromatic radicals can bepartially or completely hydrogenated and chiral carbon atoms can havethe R— or S-configuration, and its salts with pharmaceuticallyacceptable acids;Ac-D-Nal(2)¹-D-(pCl)Phe²-D-Pal(3)³-Ser⁴-Tyr⁵-D-Xxx⁶-Leu⁷-Arg⁸-Pro⁹-D-Ala¹⁰-NH₂   (V) in whichD-Xxx is an amino acid group of the general formula (VI)

in which n is the number 3 or 4, R⁴ is a group of the formula (II)

in which p is an integer from 1 to 4, R⁵ is hydrogen or an alkyl groupand R⁶ is an unsubstituted or substituted aryl group or heteroarylgroup, or R⁴ is a ring of the general formula (III)

in which q is the number 1 or 2, R⁷ is a hydrogen atom or an alkylgroup, R⁸ is a hydrogen atom or an alkyl group and X is an oxygen orsulphur atom, and its salts with pharmaceutically acceptable acids; andA-Xxx¹-Xxx²-Xxx³-Xxx⁴-Xxx⁵-Xxx⁶-Xxx⁷-Xxx⁸-Xxx⁹-Xxx¹⁰-NH₂   (VII) inwhich A is an acetyl or a 3-(4-fluorophenyl)propionyl group, Xxx¹ isD-Nal(1) or D-Nal(2), Xxx²-Xxx³ is D-Cpa-D-Pal(3) or a single bond, Xxx⁴is Ser, Xxx⁵ is N-Me-Tyr, Xxx⁶ is D-Cit, D-Hci or a D-amino acid groupof the general formula (VIII)

in which n is the number 3 or 4, where R¹¹ is a group having the generalformula (IX)—(CH₂)_(p)—CO—NR¹²R¹³   (IX) where p is an integer from 1 to 4, R¹² ishydrogen or an alkyl group and R¹³ is an unsubstituted or substitutedaryl group or heteroaryl group, or R¹¹ is a3-amino-1,2,4-triazole-5-carbonyl group or R¹¹ is a ring of the generalformula (X)

in which q is the number 1 or 2, R¹⁴ is a hydrogen atom or an alkylgroup, R¹⁵ is a hydrogen atom or an alkyl group and X is an oxygen orsulphur atom, Xxx⁷ is Leu or Nle, Xxx⁸ is Arg or Lys(iPr), Xxx⁹ is Proand Xxx¹⁰ is Ala or Sar, and their salts with pharmaceuticallyacceptable acids.
 39. The method of claim 38, wherein A-75998 is thepeptide Detirelix with the sequenceAc-D-Nal-D-(pCl)-Phe-D-Pal-Ser-NMeTyr-D-Lys(Nic)-Leu-Lys(iPr)-Pro-D-Ala-NH₂.40. The method of claim 30, wherein said pharmaceutical composition isan injection preparation.
 41. The method of claim 30, wherein said LHRHantagonist salt is Cetrorelix in the form of its acetate, gluconate orglucuronate salt, wherein said carrier is water and wherein saidpharmaceutically acceptable acid is independently selected from gluconicacid or glucuronic acid.
 42. The method of claim 30, wherein said vialis an injection vial.